Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:15]=[CH:14][C:13]=1[C:24]([O:26]C1C=CC=CN=1)=S>O1CCCC1>[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[N:15]=[CH:14][C:13]=1[C:24](=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cccc(Br)c1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Into an oven dried flask containing magnesium turnings (0.408 g, 17 mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17 mmol ) and the reaction mixture was heated at reflux. After 2 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5 g, 4.8 mmol) was added and the stirring was continued for 1 h. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The organic layer was washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was filtered and washed with hexane to give 5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:31])[CH:20]=1)[CH3:17]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:29][CH2:30]2)[CH:22]=[C:21]([CH3:31])[CH:20]=1)[CH3:17]
Reactant: CCOc1cc(C)cc(N2CCNCC2)n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C)cc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (11 μl, 0.12 mmol) was added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(6-ethoxy-4-methyl-2-pyridyl)piperazine (26 mg, 0.12 mmol) and TEA (42 μl, 0.3 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 12 mg of a solid (0.036 mmol, yield 30%).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH:8]([CH3:10])[CH3:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:11][C:12]1[N:17]=[C:16]([S:18][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH:8]([CH3:10])[CH3:9])[N:15]=[C:14]([OH:19])[CH:13]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)c1ncsc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2scnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole (5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (510 mg, 3.6 mmol), and triethylamine (2.2 mL, 15.8 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL). The solid material was dried in vacuo, affording the title compound (565 mg, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6.8 Hz), 2.24 (s, 3H), 3.27 (m, 1H), 4.61 (s, 2H), 6.03 (s, 1H), 8.84 (s, 1H); M+282.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][CH2:14][C:15]([OH:17])=O.[Cl:18][C:19]1[CH:20]=[C:21]([NH2:33])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:33][C:15](=[O:17])[CH2:14][NH:13][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: O=C(O)CNc1ccc(OC(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(OC(F)(F)F)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethoxy-phenyl-amino)-acetic acid (Example 165b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OCC)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[CH:15][NH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)sc3c2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1[nH]cnc1CCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.2 %

Procedure:
A mixture of 2-amino-6-[2-(5-methyl-1-tritylimidazol-4-yl)ethyl]benzothiazole (1.4 g) in anisole (1.4 ml) and trifluoroacetic acid (6.0 ml) was stirred for 5 hours at ambient temperature. To the reaction mixture was added a diethyl ether, and precipitate was collected by filtration. To the precipitate was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by a column chromatography on alumina eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-amino-6-[2-(5-methylimidazol-4-yl)ethyl]benzothiazole (0.24 g).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])C.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid ethyl ester (1.3 g, 2.7 mmol) in tetrahydrofuran (10 mL), methanol (10 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.57 g, 13.3 mmol). The reaction was stirred at ambient temperature for 12 hours, then made acidic by the addition of 1 M hydrochloric acid. The solution was then extracted with methylene chloride and the organic layer was dried over magnesium sulfate. Concentration in vacuo gave the title compound (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38](Cl)(Cl)=[O:39].N1C=CC=CC=1.Cl.C[O:50][C:51](=O)[CH2:52][NH:53][CH3:54]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]3[C:51](=[O:50])[CH2:52][N:53]([CH3:54])[C:38]3=[O:39])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N4C(=O)CN(C)C4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (53 mg in 2 mL dry methylene chloride) at 0° C. was added phosgene (0.077 mL of a 1.93 M solution in toluene) followed by 0.016 mL of pyridine and the mixture stirred for 1 hour at 0° C. At this time, 70 mg of sarcosine methyl ester hydrochloride was added and the mixture allowed to warm to room temperature. After 20 hours, the mixture was diluted with ethyl acetate (15 mL) and the reaction quenched by the addition of 10% citric acid. The organic portion was concentrated in vacuo to provide the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]([N:30]=[CH:31][N:32](C)C)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:38]N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]3[NH:38][N:32]=[CH:31][N:30]=3)=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=NC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ncn[nH]3)cc2)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A mixture of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide (7.0 mg, 0.014 mmol) and hydrazine hydrate (5 mg, 0.1 mmol) in acetic acid (200 μL) is stirred at 90° C. for 1 h and cooled down to room temperature. The solvent is removed under vacuum and residue is treated with saturated aqueous NaHCO3 solution (1 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated. The residue is purified by preparative thin layer chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the titled compound 5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ(ppm) 8.40(s, 1H), 8.34(s, 1H), 8.15(d, 2H), 8.03(d, 2H), 7.51(t, 2H), −7.45 (d, 2H), 7.34 (t, 1H), 7.31(d, 2H), 7.11(d, 2H); HPLC-MS calculated for C25H16ClN7O (M+H+): 466.1. Found: 466.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[Na+].[CH3:12][O:13][C:14]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[C:15]=1/[CH:16]=[CH:17]/[S:18]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)(=[O:20])=[O:19]>CO>[CH3:12][O:13][C:14]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[C:15]=1[CH:16]=[CH:17][S:18]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:27]=1)(=[O:20])=[O:19]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Reactant: COC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNc1cc(CS(=O)(=O)C=Cc2c(OC)cc(OC)cc2OC)ccc1OC
Yield: 85 %

Procedure:
To a stirred solution of methyl bromoacetate (5 mmol) and sodium acetate (5 mmol) in methanol (20 mL) was added (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine (1 mmol). The resulting mixture was heated to reflux temperature. The heated mixture was stirred at reflux temperature for 12 to 15 h. The heated mixture was then cooled and poured onto water ice (about 100 g). A precipitate formed. The precipitate was separated by filtration to provide the product in 85% yield. m.p. 182-185° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.Cl[C:37]1[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.N1C(C)=CC=CC=1C>CC#N>[CH:31]1([N:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:37]3[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: Clc1cc(Cl)ncn1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 154 using (3S*,5R*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester and 4,6-dichloropyrimidine followed by deprotection of Boc using TMSOTf and 2,6-lutidine. MS: 497 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.77 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:15])=O>>[ClH:15].[CH2:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ccnc(CO)c1
Product: CCCCc1ccnc(CCl)c1
Product: Cl
Reaction time: 4 h
Yield: 69.9 %

Procedure:
4-n-Butyl-2-hydroxymethylpyridine (28.9 g) is added dropwise, in the course of 12 minutes, to thionyl chloride (64 g) whilst allowing the temperature to rise gradually to 65° C. The reaction mixture is subsequently stirred for 4 hours under reflux and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 75° C. The resulting residue (45 g) is cautiously taken up in distilled water (350 cc) and extraction is carried out twice with diethyl ether (250 cc in total). The aqueous solution is rendered alkaline with 2 N sodium hydroxide solution (135 cc) and extraction is carried out with diethyl ether (200 cc). The ether solution is dried over anhydrous sodium sulphate and filtered, a 3 N solution of hydrogen chloride in ethanol (100 cc) is added and the mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 70° C. 4-n-Butyl-2-chloromethylpyridine hydrochloride (26.9 g), melting at 95° C., is thus obtained.
Reaction SMILES: C(OC([N:11]([C:21]1[C:22]([C:33]([O:35][CH3:36])=[O:34])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:21]2[C:22]([C:33]([O:35][CH3:36])=[O:34])=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2ccc(C)cc2)csc1-c1ccc(C)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)c2ccc(C)cc2)csc1-c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
10% Pd/C is added to compound 179 in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 30 min The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 180.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH:45]1[CH2:50][CH2:49]C[CH2:47][CH2:46]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH:15]3[CH2:49][CH2:50][CH2:45][CH2:46][CH2:47]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC3CCCCC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (bromomethyl)cyclohexane and isolated as white solid (6.1 mg, 39%). MS (m/e): 379.4 (MH+).
Reaction SMILES: [SH:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1.O.[CH3:16]I.CO>[OH-].[Na+]>[CH3:16][S:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1
Reactant: CI
Reactant: CCC1(c2nnc(S)n(N)c2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(c2nnc(SC)n(N)c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 g of 3-mercapto-4-amino-6-(1-ethylcyclopropyl)-1,2,4-triazin-5(4H)-one is dissolved in 14.2 ml of 2 N NaOH and 20 ml of H2O in the cold state. To the solution is added a solution consisting of 4.8 g of methyl iodide and 35 ml of CH3OH. The solution is stirred for 3 hours at room temperature; H2O is added and the solution is subsequently extracted 3 times with 50 ml of ethyl acetate each time. The organic phase is separated, dried, and evaporated to dryness. The residue (5.7 g) is recrystallized from 0 ml of toluene/petroleum ether (40°-65° C.)=1:1. There is thus obtained 4 g of white crystals of the formula ##STR3## having a melting point of 93°-95° C. The n-propyl derivative can be prepared in a similar manner.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])[NH:19][C:18]3[CH:28]=[CH:29][CH:30]=[N:31][C:17]2=3)=[O:15])[CH2:9][CH2:8]1)[CH3:2].[C:32]([Cl:40])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[ClH:40].[ClH:40].[C:32]([CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])[NH:19][C:18]3[CH:28]=[CH:29][CH:30]=[N:31][C:17]2=3)=[O:15])[CH2:9][CH2:8]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Solvent: CCOC(C)=O
Product: Cl
Product: O=C(CCNCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1)c1ccccc1
Yield: 62 %

Procedure:
Prepared analogously to Example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and benzoic acid chloride. The free base is dissolved in ethyl acetate and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid. The desired compound is obtained in a yield of 62% by recrystallisation from ethanol.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[N-:8]=[N+:9]=[N-:10].[Li+].O>CN(C)C=O>[N:8]([CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OCCC1Br
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-γ-butyrolactone are dissolved in 2 ml of dimethylformamide and treated at 0° C. with 612 mg (12.5 mmol) of lithium azide. The mixture is stirred at room temperature for 2 h, treated with water and extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(C)ccc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 2-Fluoro-4-methyl-1-nitro-benzene (756 mg, 4.87 mmol) are dissolved in 20 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:37][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2sc(-n3cnc4cc(OC)c(OC)cc43)nc2-c2cccc(Cl)c2)c1
Yield: 86.6 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 3-anisidine (12.3 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (3-methoxy-phenyl)-amide (45.1 mg, 86.6%) as a white solid. MS m/z 521 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.Cl.[CH2:22](O)[CH3:23]>>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[S:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[CH3:23]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2
Agent: Cl
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2

Procedure:
40 g of 6,11-dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid are boiled at reflux for 45 minutes together with 400 cc of 3 N hydrochloric acid in ethanol. The reaction mixture is completely concentrated by evaporation at reduced pressure and the oily residue is divided between ethyl acetate and water; the organic phase is washed with a 10% sodium bicarbonate solution and with water. After drying over sodium sulphate and concentrating, 6,11-dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester crystallizes by the addition of ether. (M.P. 98°-100°).